One of the research goals highlighted in the Action Plan for Liver Disease of the National Institutes of Health is to develop means, including anti-viral antibodies, to prevent recurrence of hepatitis C virus (HCV) after liver transplantation. HCV-associated liver failure is the most common indication for liver transplantation but recurrent HCV invariably occurs after transplantation and can lead to rapid graft loss. The immunosuppressed liver transplant recipients tolerate the side effects of IFN-a and ribavirin poorly and therefore new strategies for prevention and/or treatment of HCV in the transplant setting are urgently required. The long-term objective of this application is to develop an effective and tolerable antibody cocktail to prevent recurrent HCV, and the same treatment may also be useful in preventing infection in the cases of accidental virus exposure of healthcare/laboratory workers, or in high risk populations. The specific aims are (i) to generate a large panel of human monoclonal antibodies (MAbs) and to identify neutralizing MAbs targeting relatively conserved neutralizing viral epitopes;(ii) to engineer the MAbs to maximize their antiviral activity and to investigate the benefits of MAb combinations over single MAbs in neutralizing diverse HCV isolates;and (iii) to demonstrate the efficacy of the best MAb combination in protecting a small chimeric animal model bearing primary human hepatocytes against challenges by multiple heterologous HCV. A demonstration of significant protection by the antibody cocktail would provide the scientific foundation for further investigation of this passive antibody approach in the prevention of recurrent HCV in clinical settings. Public Health Relevance: Hepatitis C virus (HCV)-associated liver failure is the most common indication for liver transplantation. An effective and tolerable means to prevent re-infection after liver transplant for HCV is urgently needed. The goal of this proposal is to discover a cocktail of highly potent human monoclonal antibodies to prevent recurrent HCV.